PI(4,5)P2-dependent regulation of endothelial tip cell specification contributes to angiogenesis

Dynamic positioning of endothelial tip and stalk cells, via the interplay between VEGFR2 and NOTCH signaling, is essential for angiogenesis. VEGFR2 activates PI3K, which phosphorylates PI(4,5)P2 to PI(3,4,5)P3, activating AKT; however, PI3K/AKT does not direct tip cell specification. We report that PI(4,5)P2 hydrolysis by the phos-phoinositide-5-phosphatase, INPP5K, contributes to angiogenesis. INPP5K ablation disrupted tip cell specifica-tion and impaired embryonic angiogenesis associated with enhanced DLL4/NOTCH signaling. INPP5K degraded a pool of PI(4,5)P2 generated by PIP5K1C phosphorylation of PI(4)P in endothelial cells. INPP5K ablation in-creased PI(4,5)P2, thereby releasing II-catenin from the plasma membrane, and concurrently increased PI(3,4,5)P3-dependent AKT activation, conditions that licensed DLL4/NOTCH transcription. Suppression of PI(4,5)P2 in INPP5K-siRNA cells by PIP5K1C-siRNA, restored II-catenin membrane localization and normalized AKT signaling. Pharmacological NOTCH or AKT inhibition in vivo or genetic II-catenin attenuation rescued an-giogenesis defects in INPP5K-null mice. Therefore, PI(4,5)P2 is critical for II-catenin/DLL4/NOTCH signaling, which governs tip cell specification during angiogenesis.

Automated summary

Dynamic positioning of endothelial tip and stalk cells is essential for angiogenesis, which is regulated by the interplay between VEGFR2 and NOTCH signaling. PI(4,5)P2 hydrolysis by INPP5K contributes to angiogenesis by regulating tip cell specification and DLL4/NOTCH signaling. The inhibition of INPP5K increases PI(4,5)P2 levels, leading to the release of II-catenin from the plasma membrane and activation of AKT signaling, which enhances DLL4/NOTCH transcription.